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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0169
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 7 2507-2514
Copyright © 2008 by The Endocrine Society

Growth Hormone Deficiency by Growth Hormone Releasing Hormone-Arginine Testing Criteria Predicts Increased Cardiovascular Risk Markers in Normal Young Overweight and Obese Women

Andrea L. Utz, Ami Yamamoto, Linda Hemphill and Karen K. Miller

Neuroendocrine Unit (A.L.U., A.Y., K.K.M.) and Department of Cardiology (L.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Karen K. Miller, Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: kkmiller{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Little is known about the relationship between GH and cardiovascular risk markers in women without organic hypothalamic/pituitary disease.

Objective: The objective of the study was to determine whether healthy young overweight and obese women, who would be classified as having GH deficiency (GHD) based on standard criteria used in hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml), have increased cardiovascular risk markers.

Design: This was a cross-sectional study.

Setting: The study was conducted at the General Clinical Research Center.

Study Participants: Forty-five women of reproductive age, mean age 33.1 ± 1.2 yr and mean body mass index (BMI) 30.9 ± 1.0 kg/m2.

Intervention: There was no intervention.

Main Outcome Measures: Measures included carotid intima-medial thickness, high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, E-selectin, soluble intercellular adhesion molecule-1, TNF-{alpha} receptor I, TNF-{alpha} receptor II, fasting insulin levels, and oral glucose tolerance testing.

Results: Twenty-six percent of overweight or obese subjects and none with BMI less than 25 kg/m2 met criteria for GHD. Subjects who met GHD criteria had a mean BMI of 37.0 ± 1.7 kg/m2 (range 28.6–43.6 kg/m2), and their mean waist circumference (110.1 ± 3.5 cm) was higher than in overweight/obese women with GH sufficiency (P = 0.007). Mean carotid intima-media thickness, hsCRP, soluble intercellular adhesion molecule-1, TNF-{alpha} receptor I, and TNF-{alpha} receptor II levels were higher, and HDL lower, in women meeting GHD criteria than in GH sufficiency. Differences in HDL, hsCRP, and TNF-{alpha} receptor II remained after controlling for age plus BMI, waist circumference, or trunk fat. There were no differences in measures of insulin resistance.

Conclusions: There may be a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Hypopituitarism is associated with increased cardiovascular mortality, women are disproportionally affected, and GH deficiency (GHD) has been posited as a contributory factor (1, 2, 3, 4, 5). The increased mortality is reflected in elevated cardiovascular risk markers, including high-sensitivity C-reactive protein (hsCRP) and carotid intima-media thickness (IMT), in both women and men with GHD due to hypopituitarism (5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Moreover, GH replacement results in improvements in these markers (12, 15, 16, 17, 18, 19). However, little is known about whether the association between decreased GH secretion and increased cardiovascular risk markers observed in patients with GHD and hypopituitarism occurs in overweight and obese men and women without organic hypothalamic or pituitary disease. Although it is known that obesity is associated with reduced GH secretion, the association of cardiovascular risk marker levels with diminished GH secretion has been primarily investigated in obese men and women older than 50 yr. These studies, which have focused on traditional lipid and lipoprotein analyses, have demonstrated inverse associations of IGF-1 and GH secretion with low-density lipoprotein (LDL) cholesterol and triglycerides and positive associations with high-density lipoprotein (HDL) cholesterol (20). However, well-established predictors of cardiovascular events representing other atherogenic pathways, including hsCRP and carotid IMT, have not been studied. Whether there is a relative GHD syndrome in overweight or obese men and women that confers an increased risk of cardiovascular events, independent of increased weight itself, is unknown. Moreover, data in women of reproductive age are particularly lacking, and it is important to identify risk factors for future cardiovascular disease in this population. We therefore studied 45 healthy women of reproductive age with GHRH-arginine stimulation testing, IGF-1 levels, and cardiovascular risk markers, including hsCRP and carotid IMT, to investigate whether peak GH after stimulation with GHRH and arginine, and IGF-1 predict levels of cardiovascular risk markers in healthy young women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 45 healthy female volunteers recruited from the community through advertisements. No subject had a history of a hypothalamic or pituitary disorder. All subjects had regular menses. Exclusion criteria included estrogen or glucocorticoid use, diabetes mellitus, and other chronic illnesses, including inflammatory diseases. Women more than 280 lb were excluded from participation due to the limitations of the radiology equipment.

Methods

All data were collected during two morning outpatient visits on the Massachusetts General Hospital General Clinical Research Center. Testing for each study participant included: 1) a GHRH-arginine stimulation test, 2) a 75-g oral glucose tolerance test (OGTT), performed on a different day than the GHRH-arginine stimulation test, 3) a fasting blood draw for IGF-1 and serum cardiovascular risk markers, and 4) carotid IMT. The GHRH-arginine test was performed using the standard protocol used to diagnose GHD in adults with hypopituitarism [GHRH 1 µg/kg plus arginine 0.5 g/kg (maximum 30 g) iv were administered and GH levels drawn at baseline and every 30 min for 2 h] (21). In more than 70% of cases, testing was performed in the early follicular phase of the menstrual cycle. Carotid IMT was measured by acquiring long-axis B-mode images from the distal 1 cm of the common carotid artery using a variable-frequency, 5- to 12-MHz ultrasound transducer on a Philips HDI 5000 ultrasound system (Philips Medical Systems, Bothell, WA). Images were digitized, and average carotid IMT over the length of the 1 cm segment was calculated using semiautomated edge detection software. Right and left carotids were scanned, and the average IMT of the two is reported. All scans were analyzed by one investigator (L.H.). Total body and trunk fat mass was measured by dual-energy x-ray absorptiometry using a Hologic QDR-4500 densitometer (Hologic Inc., Waltham, MA), with an accuracy error for body fat mass of 1.7% (22). Mid-waist circumference was measured as the midpoint between the iliac crest and the lowest rib. Largest waist circumference was recorded as the largest of the following four measurements: 1.) mid-waist circumference, 2.) circumference measured at the umbilicus 3.) circumference measured at the iliac crest, and 4.) circumference measured at the level of the maximum extension of the buttocks; all were taken in a horizontal plane. The study was approved by the Partners Healthcare Inc. Institutional Review Board, and written informed consent was obtained from all subjects.

Biochemical analyses

Serum samples were collected and stored at –80 C. Serum GH was measured using an immunoradiometric assay kit (Diagnostic Systems Laboratories, Inc., Webster, TX), with a sensitivity of 0.01 ng/ml, an intraassay coefficient of variation (cv) of 3.1–5.4% and an interassay cv of 5.9–11.5%. Serum IGF-1 levels were measured using an Immulite 2000 automated immunoanalyzer (Diagnostic Products Corp., Inc., Los Angeles, CA), by a solid-phase enzyme-labeled chemiluminescent immunometric assay, with an interassay cv of 3.7% (at an IGF-1 level of 75 ng/ml) to 4.2% (at an IGF-1 level of 169 ng/ml). hsCRP was measured using a latex particle-enhanced immunoturbidimetric assay on the Hitachi 917 (Equal Diagnostics, Exton, PA), with an interassay cv of less than 5.08%. Insulin was measured using an RIA kit (Linco, Research, Inc., St. Charles, MO), with a sensitivity of 2 µU/ml, with an intraassay cv of 2.2–4.4% and an interassay cv of 2.9–6.0%. E-selectin was measured by ELISA (R&D Systems, Minneapolis, MN), with an interassay cv of 5.7–8.8% and a sensitivity of 0.1 ng/ml. Soluble intercellular adhesion molecule-1 (sICAM-1) was measured by ELISA (R&D Systems), with a sensitivity of 0.35 ng/ml and an interassay cv of 6.0–10.1%. TNF-{alpha} receptor I was measured by ELISA (R&D Systems), with an interassay cv of 3.7–8.8%. TNF-{alpha} receptor II was measured by ELISA (R&D Systems), with an interassay cv of 3.6–5.1%. Total, HDL, and LDL cholesterol and triglycerides were measured using previously described methods (23).

Statistical analysis

JMP Statistical Discoveries (version 4.0.2; SAS Institute, Inc., Cary, NC) was used for statistical analyses. All variables were tested for normality using the Shapiro-Wilk test. All variables that were not normally distributed were log transformed before analysis. Means were compared with ANOVA. Univariate regression models were constructed to determine predictors of cardiovascular risk marker levels. Multivariate models using standard least-squares analysis were constructed to control for age, BMI, midwaist circumference, and trunk fat. Statistical significance was defined as a two-tailed P < 0.05. Results are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics of study subjects

Clinical characteristics of study subjects and mean baseline cardiovascular risk marker levels are shown in Table 1Go. The age range of study participants was 19–45 yr, and the body mass index (BMI) ranged from 19.2 to 43.6 kg/m2. Subjects were classified as meeting the criteria for GHD based on standard criteria used to diagnose adults with hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml) (21, 24, 25). Clinical characteristics of women classified as meeting GHD criteria vs. those who did not are presented in Table 2Go. Twenty-six percent of overweight or obese subjects met criteria for GHD, but no subjects with BMI less than 25 kg/m2 did. The group of subjects classified as meeting hypopituitary GHD criteria had a mean BMI of 37.0 ± 1.7 kg/m2, with a range of 28.6–43.6 kg/m2, and midwaist circumference of 110 ± 3 cm (mean largest waist circumference 120.0 ± 5.3 cm), significantly higher than in all subjects with GH sufficiency (P = 0.005 for midwaist circumference and P = 0.006 for largest waist circumference) and than overweight and obese women with GH sufficiency (P = 0.007 for midwaist circumference and P = 0.0006 for largest waist circumference). However, there was considerable overlap between the groups in both BMI (stimulated GH < 5 ng/ml BMI range: 28.6–43.6 kg/m2; stimulated GH ≥ 5 ng/ml BMI range: 19.2–42.3 kg/m2) and waist circumference, whether mid-waist circumference (stimulated GH < 5 ng/ml mid-waist circumference range: 95.6–127.5 cm; stimulated GH ≥ 5 ng/ml mid-waist circumference range: 69.5–122.4 cm) or largest waist circumference (stimulated GH < 5 ng/ml largest waist circumference range: 99.9–146.5; stimulated GH ≥ 5 ng/ml largest waist circumference range: 73.6–124.3 cm). The GHD group had a higher mean age than the GH-sufficient group 38.4 ± 2.1 vs. 31.8 ± 1.4, P = 0.03).


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  		TABLE 1. Clinical characteristics and cardiovascular risk marker levels

 

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  		TABLE 2. Cardiovascular risk marker levels in GH-deficient and GH-sufficient subjects

 
BMI was strongly and inversely associated with peak GH after stimulation with GHRH and arginine (R = –0.74, P < 0.0001) (Fig. 1AGo) and IGF-1 levels (R = –0.52, P = 0.0003) (Fig. 1BGo). Both of these associations remained significant after controlling for age. Age was a predictor of IGF-1 levels but not peak GH after stimulation with GHRH and arginine. IGF-1 levels correlated with peak GH after GHRH-arginine stimulation (R = 0.50, P = 0.0005).


Figure 1
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  		FIG. 1. Peak GH after stimulation with GHRH and arginine (A) and IGF-1 (B) were inversely associated with BMI.

 
Cardiovascular risk markers

Mean levels of cardiovascular risk markers were compared between the GHD and GH-sufficient groups (Table 2Go). Mean carotid IMT, hsCRP, sICAM-1, TNF-{alpha} receptor I and TNF-{alpha} receptor II levels were all higher, and HDL cholesterol lower, in subjects who would have been classified as GHD based on hypopituitary criteria, compared with GH-sufficient subjects. hsCRP, TNF-{alpha} receptor II and HDL levels remained significantly different between the two groups after controlling for age plus a measure of adiposity, whether BMI, mid-waist circumference, or trunk fat (Table 2Go) (hsCRP: P = 0.006 after controlling for age and BMI, P = 0.007 after controlling for age and waist circumference, and P = 0.01 after controlling for age and trunk fat; TNF-{alpha} receptor II: P = 0.005 after controlling for age and BMI, P = 0.009 after controlling for age and waist circumference, and P = 0.009 after controlling for age and trunk fat; HDL cholesterol: P = 0.02 after controlling for age and BMI, P = 0.05 after controlling for age and waist circumference, and P = 0.04 after controlling for age and trunk fat). Sixty-seven percent of GHD and 28% of GH-sufficient (38% of GH-sufficient overweight or obese women) had high-risk hsCRP levels [>3 mg/liter (26)]; no woman with BMI less than 25 kg/m2 had an hsCRP level in the high-risk range. There were no differences between the groups in any measures of insulin resistance.

Peak GH after stimulation with arginine and GHRH was inversely associated with carotid IMT (R = –0.41, P = 0.005) (Fig. 2Go), hsCRP (R = –0.55, P < 0.0001) (Fig. 3AGo), TNF-{alpha} receptor II (R = –0.44, P < 0.0001) (Fig. 3BGo), sICAM-1 (R = –0.43, P = 0.004) (Fig. 3CGo), and E-selectin (R = –0.26, P = 0.088) (trend) (Fig. 3DGo). IGF-1 levels were significantly and negatively associated with the following cardiovascular risk markers: TNF-{alpha} receptor II (R = –0.33, P = 0.029), TNF-{alpha} receptor I (R = –0.37, P = 0.013), and E-selectin (R = –0.33, P = 0.03). There was a trend toward an association between IGF-1 and hsCRP (R = –0.28, P = 0.06). IGF-1 levels were not significantly associated with carotid IMT or sICAM-1.


Figure 2
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  		FIG. 2. Peak GH after stimulation with GHRH and arginine was inversely associated with carotid IMT.

 

Figure 3
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  		FIG. 3. hsCRP (A), TNF-{alpha} receptor II (B), sICAM-1 (C), and E-selectin (D) were inversely associated with peak GH after stimulation with GHRH and arginine.

 
Measures of insulin resistance were inversely associated with peak GH levels after stimulation [vs. fasting glucose (R = –0.36, P = 0.017); vs. glucose 2 h after OGTT (R = –0.55, P = 0.0002); vs. area under the curve (AUC) glucose (R = –0.39, P = 0.012) (Fig. 4AGo); vs. fasting insulin (R = –0.42, P = 0.005); vs. insulin AUC (R = –0.45, P = 0.0045) (Fig. 4BGo). In contrast, IGF-1 was associated (inversely) with fasting glucose levels only (R = –0.32, P = 0.038) and was not associated with any other measures of insulin resistance, including glucose or insulin AUC (Fig. 4Go, C and D). All cardiovascular risk markers tested were significantly associated with BMI, with correlation coefficients ranging from 0.13 to 0.28.


Figure 4
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  		FIG. 4. Glucose AUC during 2-h OGTT (A) and insulin AUC (B) were inversely associated with peak GH after stimulation with GHRH and arginine. Neither AUC glucose (C) nor AUC insulin (D) was associated with IGF-1 levels.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We demonstrate that 26% of apparently healthy overweight and obese women of reproductive age meet standard diagnostic criteria used to diagnose GHD in hypopituitarism (21). Importantly, we also demonstrate that meeting such criteria is associated with a deleterious cardiovascular marker risk profile. This includes increases in nontraditional predictors of future cardiovascular events, including carotid IMT and hsCRP, and decreases in the traditional lipoprotein maker, HDL cholesterol. Moreover, we report strong inverse associations of GH peak after stimulation by GHRH and arginine with cardiovascular risk markers in a group of healthy women with a range of weights. Our findings link low peak GH after GHRH-arginine stimulation to elevations in cardiovascular risk markers that are established to be strong predictors of future cardiovascular events, including carotid IMT and hsCRP, in young overweight and obese women. These data raise the question of whether decreased endogenous GH secretion may contribute to an elevated risk of future cardiovascular events in young overweight and obese women. Further studies are warranted to investigate this hypothesis.

GHD is thought to be an important contributory factor to the increased risk of cardiovascular events and mortality in women and men with hypopituitarism (27, 28), and GH replacement results in improvements in cardiovascular risk markers in this population (12, 15, 16, 17, 18, 19). Although studies have demonstrated that being overweight or obese in the absence of hypopituitarism is associated with decreased GH secretion (29, 30, 31, 32, 33, 34, 35), little is known about the association of endogenous GH with cardiovascular risk markers in such women. A few studies have examined the relationship between reduced GH secretion and traditional cardiovascular risk markers, specifically lipids and lipoproteins, in healthy obese women; however, it is not known whether low endogenous GH levels in obesity are associated with elevations in inflammatory cardiovascular risk markers and formation of arterial plaque. In two studies, both in subjects older than those studied in our protocol, GH levels were shown to be inversely related to lipid and lipoprotein levels. In a report by Weltman et al. (35) women older than 60 yr were studied with 24-h GH frequent sampling, and inverse associations between mean GH levels and both lipid and lipoprotein levels were demonstrated. In addition, Carmichael et al. (20) performed GHRH-arginine stimulation testing and measured cardiovascular risk markers in 86 male and female volunteers aged 50–90 yr old. They also demonstrated inverse relationships between peak GH and both LDL cholesterol and triglycerides, whereas a positive association was observed with HDL cholesterol; they also reported a correlation between insulin and peak GH levels.

To our knowledge, our investigation is the first to demonstrate an association between carotid IMT and peak GH after stimulation and to focus on apparently healthy eumenorrheic women of reproductive age. Moreover, relationships with inflammatory and adhesion markers have not been previously reported, except for hsCRP in our previous study in a small group of healthy women, which included postmenopausal women (32), and therefore, associations in premenopausal women could not be isolated. Carotid IMT and hsCRP have been shown to be particularly important predictors of cardiovascular events. Carotid IMT is a structural measure of atherogenesis and an accurate predictor of cardiovascular events (36). In an open-label study, GH administration has been shown to result in a marked decrease in carotid IMT in patients with GHD due to hypopituitarism (6), but the effects of GHD and replacement on carotid IMT in normal overweight or obese women has not been investigated. hsCRP is the most validated inflammatory marker and has been shown to be a stronger predictor of cardiovascular events than LDL cholesterol (37). In the Physician’s Health Study, baseline hsCRP levels in the highest quartile predicted a 3-fold increased risk of myocardial infarction and 2-fold increased risk of stroke, independent of other cardiovascular risk factors (38). Although most studies focus on men, a large cohort of women has been studied in the Women’s Health Initiative Observational Study (39), which demonstrated that elevated hsCRP levels predicted a 2-fold increase in risk of developing coronary heart disease in women.

We show in this study that healthy women of reproductive age with peak GH levels of less than 5 ng/ml after GHRH and arginine stimulation, a standard criterion used to diagnose GH deficiency in women with hypopituitarism (21), is associated with increased carotid IMT and hsCRP levels. Additional markers in the inflammatory pathway, including sICAM-1 (an adhesion marker) and TNF-{alpha} receptor II were elevated in patients with peak GH levels less that 5 ng/ml, and HDL was low in this group. hsCRP and TNF-{alpha} receptor II levels remained significantly higher, and HDL significantly lower, in women with stimulated GH levels less than 5 ng/ml, even after controlling for age, and BMI or trunk fat. This suggests that there may be a relative GHD syndrome associated with increased cardiovascular risk, in the absence of organic hypothalamic or pituitary disease, in apparently healthy overweight and obese women.

We observed strong relationships between peak GH after stimulation and carotid IMT, measures of insulin resistance and hsCRP. In contrast to the strong inverse associations observed between cardiovascular risk markers and peak GH after stimulation, our data demonstrate weaker associations with IGF-1 levels. We observed no statistical relationship between IGF-1 and carotid IMT or insulin resistance, and although there tended to be an inverse association between hsCRP and IGF-1, it was not statistically significant. Our data are consistent with a published study by Maccario et al. (40), which did not find an association between IGF-1 levels and traditional lipid or lipoproteins markers in 286 patients, male and female combined, aged 18–71 yr, all of whom were obese; additional cardiovascular risk markers were not studied. These data raise the question of whether there may be effects of GH on cardiovascular risk that are independent of those of IGF-1. Although most effects of GH are mediated by IGF-1, direct effects of GH have been demonstrated on a few end points. Most notable are GH’s independent lipolytic and antiinsulin effects (41, 42, 43, 44, 45). In contrast to what would be predicted from the known actions of these hormones, we showed inverse associations between measures of insulin resistance and peak GH after stimulation and no relationship between IGF-1 and measures of glucose homeostasis. Therefore, the inverse relationship between GH and measures of insulin resistance observed in our study may be mediated by indirect effects of GH and IGF-1 action, such as body composition. Further studies are warranted.

A limitation of our study is that statistical testing of cross-sectional data cannot determine the extent to which decreased peak GH after GHRH-arginine stimulation and BMI or trunk fat may be independent predictors of elevations in cardiovascular risk markers because these variables are colinear, i.e. tightly correlated with each other. However, when we divided the group into those women who met GHD criteria and those who did not, several important cardiovascular risk marker levels differed between the groups, even after controlling for age and BMI, waist circumference or trunk fat with multivariate modeling. This suggests that meeting hypopituitarism criteria for GHD may be an independent predictor of cardiovascular risk in overweight and obese women.

These results raise the additional, unanswered, question of whether GH replacement will improve cardiovascular risk marker levels in obese women of reproductive age and low endogenous GH levels. A few small interventional studies in obese men and women have yielded results that are consistent with the hypothesis that GH replacement may improve a number of cardiovascular risk markers in obese men and women with low endogenous GH secretion. In two studies, one of postmenopausal women and one of men, GH replacement resulted in decreases in mean total and LDL cholesterol without causing a deterioration in insulin resistance; in addition, hsCRP and IL-6 decreased in postmenopausal women receiving GH (46, 47, 48). The combination of GH and caloric restriction in 40 obese patients, men and women with a mean age in the mid-30s, led to decreased weight and body fat and increased HDL cholesterol (49) but no change in hsCRP (50). In another study, GH, as an adjunct to caloric restriction and exercise, resulted in reductions in total cholesterol, triglycerides, free fatty acids, fibrinogen, and plasminogen activator inhibitor-1 in type 2 diabetics with poor glycemic control (51). Further studies are needed to investigate the hypothesis that lower endogenous GH secretion may contribute to an adverse cardiovascular risk profile in overweight and obese men and women and to determine whether GH replacement may ameliorate some of these abnormalities.

In summary, to our knowledge, our data are the first to demonstrate inverse associations between peak stimulated GH and cardiovascular risk markers, other than traditional lipids and lipoproteins, in otherwise healthy women of reproductive age. This includes carotid IMT, an anatomical and important predictor of future cardiovascular events (36), which has not previously been shown to be associated with GHD in women without organic pituitary or hypothalamic disease. It also includes hsCRP, an inflammatory cardiovascular risk marker, which is a stronger predictor of cardiovascular events than LDL cholesterol (52). In addition, we raise the question of whether there is a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers an increased risk of a deleterious cardiovascular risk profile. It is not known whether GH replacement in growth hormone deficient women of reproductive age, but without organic hypothalamic or pituitary disease, would result in improvements in cardiovascular risk markers and a decrease in cardiovascular events and whether the effects on insulin resistance would be positive or deleterious. Therefore, routine screening in a clinical setting for GHD in overweight and obese women is not indicated, and GH is not approved by the Food and Drug Administration for this indication. Rather, our data suggest that further study of these issues is warranted.


   Acknowledgments
 
We thank the nurses and bionutritionists of the Massachusetts General Hospital General Clinical Research Center and the patients who participated in the study.


   Footnotes
 
This work was supported by Grants HL077674 and MO1 RR01066.

The authors have no conflicts of interest to declare.

First Published Online April 29, 2008

Abbreviations: AUC, Area under the curve; BMI, body mass index; cv, coefficient of variation; GHD, GH deficiency; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IMT, intima-media thickness; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; sICAM-1, soluble intercellular adhesion molecule-1.

Received January 23, 2008.

Accepted April 18, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Bates AS, Van’t Hoff W, Jones PJ, Clayton RN 1996 The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 81:1169–1172[Abstract]
  2. Bulow B, Hagmar L, Eskilsson J, Erfurth EM 2000 Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab 85:574–584[Abstract/Free Full Text]
  3. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
  4. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]
  5. Wuster C, Slenczka E, Ziegler R 1991 [Increased prevalence of osteoporosis and arteriosclerosis in conventionally substituted anterior pituitary insufficiency: need for additional growth hormone substitution?]. Klin Wochenschr 69:769–773[CrossRef][Medline]
  6. Borson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, Labrousse F, Pastene J, Sassolas A, Roux Y, Berthezene F 1999 Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 84:1329–1333[Abstract/Free Full Text]
  7. Capaldo B, Patti L, Oliviero U, Longobardi S, Pardo F, Vitale F, Fazio S, Di Rella F, Biondi B, Lombardi G, Sacca L 1997 Increased arterial intima-media thickness in childhood-onset growth hormone deficiency. J Clin Endocrinol Metab 82:1378–1381[Abstract/Free Full Text]
  8. Evans LM, Davies JS, Goodfellow J, Rees JA, Scanlon MF 1999 Endothelial dysfunction in hypopituitary adults with growth hormone deficiency. Clin Endocrinol (Oxf) 50:457–464[CrossRef][Medline]
  9. Johansson JO, Landin K, Tengborn L, Rosen T, Bengtsson BA 1994 High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults. Arterioscler Thromb 14:434–437[Abstract/Free Full Text]
  10. Leonsson M, Hulthe J, Oscarsson J, Johannsson G, Wendelhag I, Wikstrand J, Bengtsson BA 2002 Intima-media thickness in cariovascularly asymptomatic hypopituitary adults with growth hormone deficiency: relation to body mass index, gender, and other cardiovascular risk factors. Clin Endocrinol (Oxf) 57:751–759[CrossRef][Medline]
  11. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG 1992 Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 340:1188–1192[CrossRef][Medline]
  12. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN 1999 Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 84:453–457[Abstract/Free Full Text]
  13. Rosen T, Eden S, Larson G, Wilhelmsen L, Bengtsson BA 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:195–200[Medline]
  14. Sesmilo G, Miller KK, Hayden D, Klibanski A 2001 Inflammatory cardiovascular risk markers in women with hypopituitarism. J Clin Endocrinol Metab 86:5774–5781[Abstract/Free Full Text]
  15. Bollerslev J, Ueland T, Jorgensen AP, Fougner KJ, Wergeland R, Schreiner T, Burman P 2006 Positive effects of a physiological dose of GH on markers of atherogenesis: a placebo-controlled study in patients with adult-onset GH deficiency. Eur J Endocrinol 154:537–543[Abstract/Free Full Text]
  16. Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA 1997 Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab 82:550–555[Abstract/Free Full Text]
  17. Johansson JO, Landin K, Johannsson G, Tengborn L, Bengtsson BA 1996 Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults. Thromb Haemost 76:422–428[Medline]
  18. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P 2004 Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 89:2192–2199[Abstract/Free Full Text]
  19. Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A 2000 Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 133:111–122[Abstract/Free Full Text]
  20. Carmichael JD, Danoff A, Milani D, Roubenoff R, Lesser ML, Livote E, Reitz RE, Ferris S, Kleinberg DL 2006 GH peak response to GHRH-arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50–90. Clin Endocrinol (Oxf) 65:169–177[CrossRef][Medline]
  21. Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, Stavrou S, Kleinberg DL, Chipman JJ, Hartman ML 2002 Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 87:2067–2079[Abstract/Free Full Text]
  22. Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S 2004 Growth hormone-releasing hormone in HIV-infected men with lipodystrophy. JAMA 292:210–218[Abstract/Free Full Text]
  23. Kratz A, Ferraro M, Sluss P, Lewandrowski K 2004 Laboratory reference values. N Engl J Med 351:1548–1563[Free Full Text]
  24. Corneli G, Di Somma C, Baldelli R, Rovere S, Gasco V, Croce CG, Grottoli S, Maccario M, Colao A, Lombardi G, Ghigo E, Camanni F, Aimaretti G 2005 The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol 153:257–264[Abstract/Free Full Text]
  25. Ho KK 2007 Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol 157:695–700[Abstract/Free Full Text]
  26. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon 3rd RO, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith Jr SC, Taubert K, Tracy RP, Vinicor F 2003 Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107:499–511[Free Full Text]
  27. Besson A, Salemi S, Gallati S, Jenal A, Horn R, Mullis PS, Mullis PE 2003 Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab 88:3664–3667[Abstract/Free Full Text]
  28. Erfurth EM, Bulow B, Eskilsson J, Hagmar L 1999 High incidence of cardiovascular disease and increased prevalence of cardiovascular risk factors in women with hypopituitarism not receiving growth hormone treatment: preliminary results. Growth Horm IGF Res 9(Suppl A):21–24
  29. Buijs MM, Burggraaf J, Wijbrandts C, de Kam ML, Frolich M, Cohen AF, Romijn JA, Sauerwein HP, Meinders AE, Pijl H 2003 Blunted lipolytic response to fasting in abdominally obese women: evidence for involvement of hyposomatotropism. Am J Clin Nutr 77:544–550[Abstract/Free Full Text]
  30. Kanaley JA, Weatherup-Dentes MM, Jaynes EB, Hartman ML 1999 Obesity attenuates the growth hormone response to exercise. J Clin Endocrinol Metab 84:3156–3161[Abstract/Free Full Text]
  31. Marin P, Kvist H, Lindstedt G, Sjostrom L, Bjorntorp P 1993 Low concentrations of insulin-like growth factor-I in abdominal obesity. Int J Obes Relat Metab Disord 17:83–89[Medline]
  32. Miller KK, Biller BM, Lipman JG, Bradwin G, Rifai N, Klibanski A 2005 Truncal adiposity, relative growth hormone deficiency, and cardiovascular risk. J Clin Endocrinol Metab 90:768–774[Abstract/Free Full Text]
  33. Pijl H, Langendonk JG, Burggraaf J, Frolich M, Cohen AF, Veldhuis JD, Meinders AE 2001 Altered neuroregulation of GH secretion in viscerally obese premenopausal women. J Clin Endocrinol Metab 86:5509–5515[Abstract/Free Full Text]
  34. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G 1991 Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 72:51–59[Abstract/Free Full Text]
  35. Weltman A, Despres JP, Clasey JL, Weltman JY, Wideman L, Kanaley J, Patrie J, Bergeron J, Thorner MO, Bouchard C, Hartman ML 2003 Impact of abdominal visceral fat, growth hormone, fitness, and insulin on lipids and lipoproteins in older adults. Metabolism 52:73–80[CrossRef][Medline]
  36. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK 1999 Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22[Abstract/Free Full Text]
  37. Ridker P, Rifai N, Rose L, Buring J, Cook N 2002 Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. 2002 347:1557–1565
  38. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH 1997 Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979[Abstract/Free Full Text]
  39. Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB, Ridker PM 2002 Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA 288:980–987[Abstract/Free Full Text]
  40. Maccario M, Ramunni J, Oleandri SE, Procopio M, Grottoli S, Rossetto R, Savio P, Aimaretti G, Camanni F, Ghigo E 1999 Relationships between IGF-1 and age, gender, body mass, fat distribution, metabolic and hormonal variables in obese patients. Int J Obes Relat Metab Disord 23:612–618[CrossRef][Medline]
  41. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A 2001 The somatomedin hypothesis: 2001. Endocr Rev 22:53–74[Abstract/Free Full Text]
  42. Butler AA, Le Roith D 2001 Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol 63:141–164[CrossRef][Medline]
  43. Clemmons DR 2004 The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. J Clin Invest 113:25–27[CrossRef][Medline]
  44. Hussain MA, Schmitz O, Mengel A, Glatz Y, Christiansen JS, Zapf J, Froesch ER 1994 Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans. J Clin Invest 94:1126–1133[Medline]
  45. Dietz J, Schwartz J 1991 Growth hormone alters lipolysis and hormone-sensitive lipase activity in 3T3–F442A adipocytes. Metabolism 40:800–806[CrossRef][Medline]
  46. Franco C, Andersson B, Lonn L, Bengtsson BA, Svensson J, Johannsson G 2007 Growth hormone reduces inflammation in postmenopausal women with abdominal obesity: a 12-month, randomized, placebo-controlled trial. J Clin Endocrinol Metab 92:2644–2647[Abstract/Free Full Text]
  47. Franco C, Brandberg J, Lonn L, Andersson B, Bengtsson BA, Johannsson G 2005 Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial. J Clin Endocrinol Metab 90:1466–1474[Abstract/Free Full Text]
  48. Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof K, Bjorntorp P, Sjostrom L, Bengtsson BA 1997 Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure. J Clin Endocrinol Metab 82:727–734[Abstract/Free Full Text]
  49. Albert SG, Mooradian AD 2004 Low-dose recombinant human growth hormone as adjuvant therapy to lifestyle modifications in the management of obesity. J Clin Endocrinol Metab 89:695–701[Abstract/Free Full Text]
  50. Albert SG, Haas MJ, Mooradian AD 2007 The effects of recombinant human growth hormone (rhGH) supplementation on adipokines and C-reactive protein in obese subjects. Growth Horm IGF Res 17:19–25[CrossRef][Medline]
  51. Ahn CW, Kim CS, Nam JH, Kim HJ, Nam JS, Park JS, Kang ES, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB 2006 Effects of growth hormone on insulin resistance and atherosclerotic risk factors in obese type 2 diabetic patients with poor glycaemic control. Clin Endocrinol (Oxf) 64:444–449[Medline]
  52. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR 2002 Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557–1565[Abstract/Free Full Text]



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